CN111499642A - Pharmaceutical salt and crystal form of pyrrolo [2,3-d ] pyridazine-7-ketone derivative and preparation method thereof - Google Patents
Pharmaceutical salt and crystal form of pyrrolo [2,3-d ] pyridazine-7-ketone derivative and preparation method thereof Download PDFInfo
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Abstract
The application provides medicinal salts and crystal forms of pyrrolo [2,3-d ] pyridazine-7-one derivatives and preparation methods thereof. The BTK kinase inhibitor (R) -4-amino-1- (1- (butyl-2-alkynoyl) pyrrolidine-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazine-7-ketone salt and a crystal form and a preparation method thereof specifically provide a stable crystal form by preparation, wherein the preparation method comprises the steps of salt formation, dissolution, crystallization and the like.
Description
Technical Field
The application belongs to the technical field of pharmaceutical chemicals, and particularly relates to a BTK kinase inhibitor (R) -4-amino-1- (1- (butyl-2-alkynoyl) pyrrolidine-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazine-7-one salt, and a crystal form and a preparation method thereof.
Background
WO2016007185 discloses a compound (R) -4-amino-1- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one (compound of formula I) which is a novel BTK kinase inhibitor and is improved in kinase selectivity, clinical efficacy or indications and safety. However, the patent does not make any investigations on the crystalline forms of the compound and its salts.
Salification is one of effective means for improving the physicochemical property of the drug molecules and the pharmaceutical property of the drug molecules, can change the solubility of the drug, improve the compliance of the drug, improve the stability and the bioavailability of the drug, and reduce the adverse reaction of the drug. Generally, the crystal structure of the active ingredient of a drug and its salt not only affects the physical and chemical stability of the drug itself, but also affects the difficulty of later drug preparation, the production cost, the crystallization conditions and the storage conditions, which may cause the crystal structure of the compound and its salt to change, and sometimes may be accompanied by the generation of other crystal forms. Therefore, from the comprehensive consideration of stability, difficulty of drug preparation process, production cost and the like, we need to deeply research the crystal structure of the compound and the salt thereof so as to find out a stable crystal form with high purity, easy preparation and low production cost.
Disclosure of Invention
The present application provides a pharmaceutically acceptable salt of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one, said pharmaceutically acceptable salt being selected from the hydrochloride salt. Preferably, the ratio of the compound to the acid molecule is 1: 1.
The present application also provides a process for preparing a pharmaceutically acceptable salt of claim 1, comprising: a step of salifying a compound (R) -4-amino-1- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one with an acid selected from a hydrochloric acid or a hydrogen chloride solution, wherein the solvent used for the salifying reaction is preferably one or more of methanol, n-propanol, isopropanol, ethanol, isopropyl ether, tetrahydrofuran, isopropyl acetate, acetone, methyl tert-butyl ether, acetonitrile, 1, 4-dioxane, ethyl acetate and n-hexane.
Further, in an alternative embodiment, the method for preparing the pharmaceutically acceptable salt further comprises the steps of volatilizing the solvent or stirring for crystallization, filtering, drying and the like.
The present application also provides a pharmaceutical composition comprising the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one hydrochloride and a pharmaceutically acceptable adjuvant optionally selected from at least one of a pharmaceutically acceptable carrier, diluent or excipient.
The present application also provides a pharmaceutical composition prepared from the compound (R) -4-amino-1- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one hydrochloride and a pharmaceutically acceptable adjuvant optionally selected from at least one of a pharmaceutically acceptable carrier, diluent or excipient.
Also provided herein is the use of the aforementioned pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the manufacture of a medicament for the treatment or prevention of a disease associated with BTK kinase.
Also provided herein is the use of the aforementioned pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions in the manufacture of a medicament for the treatment or prevention of B-cell malignancies and autoimmune diseases.
The present application also provides crystalline form I of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one hydrochloride having characteristic peaks at 5.305, 6.080, 6.770, 11.110, 17.695, 24.400 and 25.525 in an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta.
In an alternative embodiment, form I described herein has characteristic peaks at 5.305, 6.080, 6.770, 11.110, 13.700, 14.335, 17.695, 20.695, 24.400, and 25.525 in an X-ray powder diffraction pattern expressed in degrees 2 θ of diffraction.
In an alternative embodiment, crystalline form I of the hydrochloride salt described herein has characteristic peaks at 5.305, 6.080, 6.770, 11.110, 13.700, 14.335, 15.855, 17.695, 19.775, 20.695, 21.855, 24.400, and 25.525 in an X-ray powder diffraction pattern expressed in degrees 2 Θ at diffraction angles.
In an alternative embodiment, crystalline hydrochloride salt I described herein has characteristic peaks at 5.305, 6.080, 6.770, 11.110, 13.700, 14.335, 15.855, 17.695, 19.775, 20.695, 21.855, 22.745, 24.400, 25.525, 27.065, and 27.520 in an X-ray powder diffraction pattern expressed in degrees 2 θ of diffraction.
Further, the X-ray powder diffraction pattern of the hydrochloride I crystal form expressed by the diffraction angle 2 theta angle is shown in figure 1.
In another aspect, the present application provides a method of preparing crystalline form I of the hydrochloride salt of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one comprising:
(1) reacting the compound (R) -4-amino-1- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one with a hydrogen chloride solution or hydrogen chloride gas in a solvent (I), or dissolving the hydrochloride salt of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one in a solvent (I); wherein the solvent (I) is selected from one or more of tetrahydrofuran, methanol, n-propanol, isopropanol, ethanol, isopropyl ether, isopropyl acetate, acetone, methyl tert-butyl ether, acetonitrile, 1, 4-dioxane, ethyl acetate and n-hexane;
(2) and (4) crystallizing.
Wherein the crystallization can be volatile solvent crystallization, stirring crystallization or cooling crystallization.
Further, in an alternative embodiment, the method of preparing the aforementioned crystalline form I of the hydrochloride salt further comprises the steps of filtering, drying, and the like.
Further, the volume (ml) of the solvent (I) used in the present method is 1 to 100 times of the weight (g) of the compound, and may be 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100 times.
Further, the solvent used in the present application to prepare the hydrogen chloride solution is selected from, but not limited to, ethanol, methanol, isopropanol, or water. Aqueous hydrogen chloride is also commonly referred to as hydrochloric acid or hydrochloric acid solution.
The application also provides a pharmaceutical composition containing the hydrochloride form I or the hydrochloride form I prepared by the method and a pharmaceutical adjuvant optionally selected from pharmaceutically acceptable carriers, diluents or excipients.
The application also provides a pharmaceutical composition prepared from the hydrochloride form I or the hydrochloride form I prepared by the method and optionally a pharmaceutical excipient from a pharmaceutically acceptable carrier, diluent or excipient.
The present application also provides a process for preparing a pharmaceutical composition comprising the step of mixing the aforementioned form I hydrochloride salt or the form I hydrochloride salt prepared by the aforementioned process with a pharmaceutically acceptable carrier, diluent or excipient.
The present application also provides the use of the aforementioned crystalline form I hydrochloride salt or crystalline form I hydrochloride salt prepared by the aforementioned methods, or the aforementioned composition, in the manufacture of a medicament for the treatment or prevention of a BTK kinase-associated disease.
The application also provides the use of the aforementioned crystalline hydrochloride form I or crystalline hydrochloride form I prepared by the aforementioned methods or the aforementioned composition in the preparation of a medicament for the treatment or prevention of B-cell malignancies and autoimmune diseases.
In another aspect, the present application also provides crystalline form II of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one.
Further, the crystalline form II of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one described herein has characteristic peaks at 5.855, 6.310, 7.030, 11.755, 12.835, 14.280 and 17.525 in an X-ray powder diffraction pattern expressed in diffraction angle 2 θ.
In an alternative embodiment, form II of the compounds described herein have characteristic peaks at 5.855, 6.310, 7.030, 11.755, 12.835, 14.280, 17.525, 17.925, 21.445, and 25.285 in an X-ray powder diffraction pattern at diffraction angle 2 θ.
In an alternative embodiment, the crystalline form II of the compound described herein, an X-ray powder diffraction pattern expressed in degrees of diffraction angle 2 Θ, has characteristic peaks at 5.855, 6.310, 7.030, 11.755, 12.835, 14.280, 17.525, 17.925, 20.090, 21.445, 23.130, 25.285, and 25.890.
In an alternative embodiment, crystalline form II of the compounds described herein, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 Θ, has characteristic peaks at 5.855, 6.310, 7.030, 8.404, 11.755, 12.835, 14.280, 16.311, 17.525, 17.925, 20.090, 21.445, 23.130, 25.285, and 25.890.
In an alternative embodiment, the crystalline form II of the compound described herein has an X-ray powder diffraction pattern, expressed in terms of diffraction angle 2 Θ angles, as shown in figure 2.
The present application also provides a process for preparing a crystalline form II of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one comprising:
(1) mixing the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one hydrochloride with the solvent (II), and dissolving with stirring or heating;
(2) mixed with a solvent (III), preferably water.
Further, in an alternative embodiment, the method for preparing the aforementioned compound II crystal form further comprises the steps of volatilizing the solvent or stirring or cooling for crystallization, filtering, drying, and the like.
In an alternative embodiment, the solvent (II) is selected from C1-6Alkyl alcohols, including but not limited to methanol, ethanol, isopropanol.
The cooling crystallization includes, but is not limited to, rapid cooling crystallization, or cooling and stirring crystallization at a certain rate, for example, cooling at 10K/min.
The application also provides a pharmaceutical composition containing the crystal form II or the crystal form II prepared by the method and a pharmaceutical adjuvant which is selected from pharmaceutically acceptable carriers, diluents or excipients.
The present application also provides a process for the preparation of a pharmaceutical composition comprising the step of mixing the aforementioned form II or form II prepared by the aforementioned process with a pharmaceutically acceptable carrier, diluent or excipient.
The present application also provides the use of the aforementioned form II or form II prepared by the aforementioned methods or the aforementioned compositions in the manufacture of a medicament for the treatment or prevention of a BTK kinase-associated disease.
The present application also provides the use of the aforementioned form II or form II prepared by the aforementioned methods or the aforementioned compositions in the manufacture of a medicament for the treatment or prevention of B cell malignancies and autoimmune diseases.
The "X-ray powder diffraction pattern" described herein is measured using Cu-K α radiation.
The term "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern of X-rays according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-rays,
order of diffractionn is any positive integer, and generally takes a first-order diffraction peak, n is 1, when X-ray is incident on an atomic plane with d lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The term "2 theta or 2 theta angle" as used herein refers to the diffraction angle, theta is the Bragg angle and is expressed in degrees or degrees; the error range of each characteristic peak 2 θ is ± 0.30, and may be-0.30, -0.29, -0.28, -0.27, -0.26, -0.25, -0.24, -0.23, -0.22, -0.21, -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.21, 0.20, 0.22, 0.23, 0.26, 0.20, preferably ± 0.20.
The term "interplanar spacing or interplanar spacing (d value)" as used herein refers to the selection of 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points of a spatial lattice, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined connecting lines of the parallelepiped units to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
The differential scanning calorimetry or DSC mentioned in the application refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance during the process of sample temperature rise or constant temperature so as to characterize all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
XRPD was X-ray powder diffraction detection: measurement was carried out using BRUKER D8 type X-rayThe light diffractometer is used for collecting information, namely Cu anode (40kV and 40mA) and Cu-K α rays
K β ray
Scanning range (2q range): 3-64 degrees, a scanning step length of 0.02 and a slit width (collimator) of 1.0 mm. A step-by-step scanning method is adopted, the number of scanning steps is 3, the scanning range of each step is 19 degrees, the starting degree is 10 degrees, the ending degree is 48 degrees, and the time length of each step is 45 s.
DSC is differential scanning calorimetry, METT L ER TO L EDO DSC 3+ differential scanning calorimeter is adopted for measurement, the temperature rise rate is 10 ℃/min, the specific temperature range refers TO a corresponding graph (mostly 25-300 or 25-350 ℃), and the nitrogen purging speed is 50m L/min.
In the present application, the drying temperature is generally 25 ℃ to 100 ℃, preferably 40 ℃ to 70 ℃, and the drying can be carried out under normal pressure or reduced pressure.
The reagents used in the present invention are commercially available or self-prepared according to the literature, for example, (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one (hereinafter referred to as Compound A) prepared according to the method of the literature CN107406453B for use.
Drawings
FIG. 1: an XRPD pattern for crystal form I of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one hydrochloride.
FIG. 2: an XRPD pattern for a crystalline form II of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one.
Detailed Description
The present application is used to further describe the technical solutions by combining the following examples, but the scope of the present application is not limited by these examples.
Example 1: compound A hydrochloride
Hydrogen chloride solution was prepared for use: transferring 0.1ml of concentrated hydrochloric acid, adding 9.9ml of ethanol, and shaking up to prepare an ethanol hydrochloric acid solution for later use;
free compound A (100mg) was weighed, 5ml of n-hexane was added, 1.8ml of ethanolic hydrochloric acid solution was added, stirring was conducted with heating at 50 ℃, filtration, washing with n-hexane, and drying were carried out, and the crystalline product showed an XRPD pattern as shown in FIG. 1 and characteristic peak positions as shown in Table 1 below, and a DSC pattern having an endothermic peak at 173.8 ℃.
TABLE 1
Test one: stability study
The compound A hydrochloride crystal form I is laid flat, the stability of samples under different temperature or/and humidity conditions is inspected, the sampling inspection period is 7 days, 14 days and 2 months, and the specific data are shown in a table 2:
TABLE 2
The results show that: the I crystal form of the hydrochloride of the compound A has excellent physical and chemical stability under different conditions and good medicinal properties.
Example 2: compound A hydrochloride
Adding compound A (100mg) into 5ml tetrahydrofuran solution, adding concentrated hydrochloric acid 18ul, heating and stirring at 50 deg.C, filtering, washing with tetrahydrofuran, and drying to obtain solid. The hydrochloride is detected as I crystal form by XRPD.
Example 3: crystal form II of compound A
Adding compound A hydrochloride (60mg) into 0.6ml methanol solution, stirring for dissolving, adding 0.3ml water, heating to 25 ℃, cooling to 5 ℃ at the speed of 10K/min, stirring for crystallization, filtering, and drying at 50 ℃ to obtain a solid sample, wherein the XRPD pattern of the crystallized product is shown in figure 2, and the characteristic peak positions are shown in the following table 3.
TABLE 3
| Peak number | 2 theta value [ ° or degree] | Relative strength% |
| 1 | 5.855 | 100 |
| 2 | 6.310 | 26.5 |
| 3 | 7.030 | 47.6 |
| 4 | 8.404 | 5.4 |
| 5 | 11.755 | 62.3 |
| 6 | 12.835 | 17.9 |
| 7 | 14.280 | 47.4 |
| 8 | 16.311 | 7.7 |
| 9 | 17.525 | 24 |
| 10 | 17.925 | 18.4 |
| 11 | 20.090 | 17.4 |
| 12 | 21.445 | 20.6 |
| 13 | 23.130 | 25 |
| 14 | 25.285 | 26.3 |
| 15 | 25.890 | 19.4 |
And detecting the content of the chloride ions, wherein the chloride ions are not contained.
DSC detection shows that: the XRPD spectrum of the sample is not changed in the temperature rising process of 25-70 ℃, and the XRPD spectrum of the sample is changed in the temperature rising process of 25-160 ℃.
Test example 2: stability study
The samples are placed evenly, the stability of the samples under different temperature or/and humidity conditions is inspected, the sampling inspection period is 7 days and 14 days, and the specific data are shown in a table 4:
TABLE 4
The results show that: the II crystal form of the compound A has excellent physical and chemical stability under different conditions and good medicinal properties.
Claims (10)
1. A pharmaceutically acceptable salt of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one, wherein said pharmaceutically acceptable salt is selected from the hydrochloride salt, preferably the ratio of compound to acid molecule is 1: 1.
2. A process for preparing a pharmaceutically acceptable salt of claim 1 comprising: a step of salifying the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one with an acid.
3. Crystalline form I of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one hydrochloride having characteristic peaks at 5.305, 6.080, 6.770, 11.110, 17.695, 24.400 and 25.525 in X-ray powder diffraction pattern expressed in angle of diffraction angle 2 θ.
4. The crystalline form I of claim 3, characterized by an X-ray powder diffraction pattern expressed in degrees of diffraction at angles 2 Θ having characteristic peaks at 5.305, 6.080, 6.770, 11.110, 13.700, 14.335, 17.695, 20.695, 24.400, and 25.525.
5. The crystalline form I of claim 3 or 4, characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 Θ angles with characteristic peaks at 5.305, 6.080, 6.770, 11.110, 13.700, 14.335, 15.855, 17.695, 19.775, 20.695, 21.855, 24.400 and 25.525.
6. The crystalline form I according to any one of claims 3 to 5, characterized by an X-ray powder diffraction pattern expressed in diffraction angle 2 Θ angles as shown in figure 1.
7. A process for preparing the crystalline form I of any one of claims 3-6, comprising:
(1) reacting the compound (R) -4-amino-1- (1- (but-2-alkynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one with a hydrogen chloride solution or hydrogen chloride gas in a solvent (I), or dissolving the hydrochloride salt of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one in a solvent (I); wherein the solvent (I) is selected from one or more of tetrahydrofuran, methanol, n-propanol, isopropanol, ethanol, isopropyl ether, isopropyl acetate, acetone, methyl tert-butyl ether, acetonitrile, 1, 4-dioxane, ethyl acetate and n-hexane;
(2) and (4) crystallizing.
8. Crystalline form II of the compound (R) -4-amino-1- (1- (but-2-ynoyl) pyrrolidin-3-yl) -3- (4- (2, 6-difluorophenoxy) phenyl) -1, 6-dihydro-7H-pyrrolo [2,3-d ] pyridazin-7-one having characteristic peaks at 5.855, 6.310, 7.030, 11.755, 12.835, 14.280 and 17.525 in X-ray powder diffraction pattern expressed in diffraction angle 2 θ.
9. A pharmaceutical composition comprising the pharmaceutically acceptable salt of claim 1, or the crystalline form I of any one of claims 3-6, or the crystalline form II of claim 8, further comprising at least one pharmaceutically acceptable excipient selected from pharmaceutically acceptable carriers, diluents, or excipients.
10. The crystalline form of any of claims 3-6 or 8, wherein the 2 Θ angle error is within a range of ± 0.20.
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| CN116813624A (en) * | 2023-06-29 | 2023-09-29 | 成都金瑞基业生物科技有限公司 | Crystal form of JAK2 inhibitor and preparation method thereof |
| CN119504758A (en) * | 2023-08-23 | 2025-02-25 | 北京普祺医药科技股份有限公司 | A crystal form of a JAK kinase inhibitor |
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